The prevalence and severity of asthma have increased dramatically in recent decades. It is generally accepted that asthma arises as a result of inappropriate immunological responses to common environmental antigens in genetically susceptible individuals (Willis-Karp, M., “Immunologic basis of antigen-induced airway hyperresponsiveness,” Ann. Rev. Immunol. 17: 255-281 (1999)). Recently, the gene encoding complement factor 5 (C5) has been identified as a susceptibility locus for allergen-induced airway hyperresponsiveness in a murine model of asthma (Karp et al., Nature Immunology 1: 221-225, 2000).
Activation of the classical, lectin complement pathways can result in proteolytic cleavage of C5 to two fragments, C5a and C5b, both of which can stimulate cytokine production. As part of a hemolytically active membrane attack complex, C5b causes signaling in neutrophils and endothelia, inducing chemokine production by the latter (Wang et al., Blood 85: 2570-2578, 1995; Wang et al., J. Immunol. 156: 786-792, 1996; Kilgore et al., Am J. Pathol. 150: 2019-2031, 1997). C5a has pleiotropic effects on inflammation, being chemotactic for all myeloid lineages, inducing degranulation and the production of a variety of proinflammatory mediators by granulocytes and increasing vascular permeability (Gerard et al., Annu. Rev. Immunol. 164: 3009-3017, 2000). C5a also stimulates monocyte and macrophage production of the proinflammatory cytokines TNF-α, IL-1 and IL-6 (Morgan et al., J. Immunol. 148: 3937-3942, 1992; Schindler et al., Blood 76: 1631-1638, 1990; Cavaillon et al., Eur. J. Immunol. 20: 253-257, 1990). Inhibition of stimulation of monocytes and macrophages by C5a through the C5a receptor has resulted in the inhibition of production of IL-12 (Karp, Nature Immun. , 2000), a Th1 promoting cytokine, by these cells.
The nascent C5a fragment of C5, once formed in blood plasma or serum, is rapidly cleaved to the C5a-desArg form by the endogenous serum carboxypeptidase N enzyme (Bokisch et al. J. Clin. Invest. 49: 2427-36, 1970).
Prior to the present invention, there is no recognition that the plasma levels of C5a or levels of C5a-desArg in asthma patients correlate with the severity of asthma.